title: Pharmacokinetics of macitentan in caucasian and Japanese subjects: the influence of ethnicity and sex.
abstract: OBJECTIVE
  Macitentan is a novel dual endothelin receptor antagonist with sustained receptor binding in clinical development for pulmonary arterial hypertension. The present study compared the pharmacokinetics and safety of macitentan in healthy Caucasian and Japanese subjects and explored the potential sex differences.
  
  
  METHODS
  In this single-center, open-label, phase I study 10 healthy subjects of each ethnic origin with a male/female ratio of 1:1 in each group were administered a single oral 10-mg dose of macitentan. Blood samples were taken to determine plasma levels of macitentan and its pharmacologically active metabolite, ACT-132577, and safety and tolerability were monitored using standard assessments.
  
  
  RESULTS
  For both macitentan and its metabolite, values for Cmax were similar but a shorter half-life was determined in Japanese subjects resulting in an exposure to both compounds being approximately 15% lower in Japanese when compared to Caucasian subjects. The exposure to macitentan was similar in Japanese males and females whereas Caucasian females had an approximately 25% higher exposure than Caucasian males. In both ethnic groups, females had an approximately 15% higher exposure to ACT-132577 than male subjects. Macitentan was well tolerated in both ethnic groups. There were no clinically significant differences in adverse event profile, clinical laboratory, electrocardiographic parameters, and vital signs between both groups.
  
  
  CONCLUSIONS
  The data suggest that the minor differences in pharmacokinetics between the two groups are not clinically relevant and no dose adjustment of macitentan based on Japanese ethnic origin or sex is necessary.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. shirin.bruderer@actelion.com
authors.forename: Shirin
authors.initials: S
authors.lastname: Bruderer
authors.forename: Joanne
authors.initials: J
authors.lastname: Marjason
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Sidharta
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000328:Adult; D044466:Asian People; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D005260:Female; D006801:Humans; D008297:Male; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012727:Sex Characteristics; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D044465:White People; D055815:Young Adult
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C572762:aprocitentan; C533860:macitentan